The invention relates to novel aryl substituted azabenzimidazoles and the pharmaceutically acceptable salts thereof, methods of preparing these compounds and the use of these compounds in the treatment of HIV, AIDS and AIDS related diseases and in slowing the progression of HIV infection into AIDS.
The human disease, Acquired Immune Deficiency Syndrome (AIDS), is caused by the Human Immunodeficiency Virus (HIV), particularly the strain known as HIV-1.
Like other viruses, HIV cannot replicate without commandeering the biosynthetic apparatus of the host cell it infects. HIV causes this biosynthetic apparatus to produce the structural proteins which make up the viral progeny. These proteins are coded for by the genetic material contained within the infecting virus particle, or virion. Being a retrovirus, however, the genetic material of HIV is RNA, not DNA as in the host cell's genome. Accordingly, the viral RNA must first be converted into DNA, and then integrated into the host cell's genome, in order for the host cell to produce the required viral proteins. The conversion of the RNA to DNA is accomplished through the use of enzyme reverse transcriptase (RT), which is included within the infecting virion along with the RNA. Reverse transcriptase has three enzymatic functions; it acts as an RNA-dependent DNA polymerase; as a ribonuclease; and as a DNA-dependent DNA polymerase. Acting first as an RNA-dependent DNA polymerase, RT makes a single-stranded DNA copy of the viral RNA. Next, acting as a ribonuclease, RT frees the DNA just produced from the original viral RNA and then destroys the original RNA. Finally, acting as a DNA-dependent DNA polymerase, RT makes a second, complementary DNA strand, using the first DNA strand as a template. The two strands form double stranded DNA, which is integrated into the host cell's genome by another enzyme called an integrase.
Compounds which inhibit the enzymatic functions of HIV reverse transcriptase will inhibit replication of HIV in infected cells. There is a high medical need for better tolerated, conveniently administered agents to treat AIDS which is increasingly viewed as a chronic disease. These agents should ideally reverse the development and progression of AIDS, in HIV infected individuals, reduce susceptibility to secondary infections, and return the patient to as near a normal lifestyle as possible.